Sohn Winnie, Lee Edward, Kankam Martin K, Egbuna Ogo, Moffat Graeme, Bussiere Jeanine, Padhi Desmond, Ng Eric, Kumar Sandeep, Slatter J Greg
Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA.
Early Development, Amgen Inc., Thousand Oaks, CA, USA.
Br J Clin Pharmacol. 2016 Feb;81(2):362-9. doi: 10.1111/bcp.12798. Epub 2015 Dec 5.
Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner.
An open-label, single-dose study in 12 healthy men was conducted over a 106-day period. Subjects received a single subcutaneous dose of 60-mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded.
Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax ) was 6170 (2070) ng ml(-1) (serum) and 100 (81.9) ng ml(-1) (seminal fluid). The median time to Cmax (tmax ) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast ) was 333 000 (122 000) day•ng ml(-1) (serum) and 5220 (4880) day•ng ml(-1) (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived 'no effect level' for denosumab.
These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.
地诺单抗是一种全人源单克隆免疫球蛋白G2抗体，可抑制骨吸收并增加骨量和骨强度。本临床研究评估了健康男性单次注射地诺单抗后的血清和精液药代动力学，并评估了在与怀孕伴侣发生无保护性行为时，精液中的地诺单抗是否会对胎儿构成任何风险。
在12名健康男性中进行了一项为期106天的开放标签单剂量研究。受试者在第1天接受了一次60毫克地诺单抗的皮下注射。在指定时间点采集血清和精液样本，以评估地诺单抗的药代动力学。记录不良事件。
精液中可检测到低浓度的地诺单抗（约为血清浓度的2%）。观察到的平均[标准差（SD）]最大药物浓度（Cmax）在血清中为6170（2070）纳克/毫升，在精液中为100（81.9）纳克/毫升。达到Cmax的中位时间（tmax）在血清中为8天，在精液中为21天。从时间零点到最后可定量浓度时间的血浆浓度-时间曲线下面积（AUC）的平均值（SD）在血清中为333000（122000）天•纳克/毫升，在精液中为5220（4880）天•纳克/毫升。精液与血清之间的平均（SD）Cmax和AUC比值分别为0.0217（0.0154）和0.0170（0.0148）。使用保守的射精量（6毫升）、阴道吸收（100%）和胎盘转运（100%）假设，测得的精液中地诺单抗平均Cmax导致的胎儿暴露量比临床前得出的地诺单抗“无效应水平”低110倍以上。
这些结果表明，通过精液转移至怀孕伴侣而使胎儿接触地诺单抗的风险可忽略不计。
